- 作者: Chih-Hsiung Hsieh, Wen-Hui Kuan, Wei-Lun Chang, I-Ying Kuo, Hsun Liu, Dar-Bin Shieh, Hsuan Liu, Bertrand Tan & Yi-Ching Wang
- 作者服務機構: 1.Department of Biochemistry, Chang Gung University, Taoyuan, 33302, Taiwan 2.Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan 3.Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 70101, Taiwan 4.Department of Pharmacology and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 70101, Taiwan, ROC 5.Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan 6.Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan 7.Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
- 中文摘要:
- 英文摘要:
Background
Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer-associated death worldwide with a dismal overall 5-year survival rate of less than 20%. The standard first-line therapy for advanced ESCC is concomitant chemo-radiation therapy (CCRT); however, patients usually develop resistance, resulting in unfavorable outcomes. Therefore, it is urgent to identify the mechanisms underlying CCRT resistance and develop effective treatment strategies.
Methods
Patients’ endoscopic biopsy tumor tissues obtained before CCRT treatment were used to perform RNA-seq and GSEA analysis. Immunohistochemical (IHC) staining, chromatin immunoprecipitation (ChIP), and promoter reporter analyses were conducted to investigate the relationship between SOX17 and NRF2. Xenograft mouse models were used to study the role of SOX17/NRF2 axis in tumor growth and the efficacy of carboxymethyl cellulose-coated zero-valent-iron (ZVI@CMC).
Results
In this study, a notable gene expression signature associated with NRF2 activation was observed in the poor CCRT responders. Further, IHC staining of endoscopic biopsy of 164 ESCC patients revealed an inverse correlation between NRF2 and SOX17, a tumor-suppressive transcription factor with low expression in ESCC due to promoter hypermethylation. Using ChIP and promoter reporter analyses, we demonstrated that SOX17 was a novel upstream transcriptional suppressor of NRF2. In particular, SOX17low/NRF2high nuclear level significantly correlated with poor CCRT response and poor survival, indicating that the dysregulation of SOX17/NRF2 axis played a pivotal role in CCRT resistance and tumor progression. Notably, the in-house developed nanoparticle ZVI@CMC functioned as an inhibitor of DNA methyltransferases to restore expression of SOX17 that downregulated NRF2, thereby overcoming the resistance in ESCC. Additionally, the combination of ZVI@CMC with radiation treatment significantly augmented anticancer efficacy to inhibit tumor growth in CCRT resistant cancer.
Conclusion
This study identifies a novel SOX17low/NRF2high signature in ESCC patients with poor prognosis, recognizes SOX17 as a transcriptional repressor of NRF2, and provides a promising strategy targeting SOX17/NRF2 axis to overcome resistance. - 中文關鍵字:
- 英文關鍵字: Chemoradiotherapy resistance, NRF2, SOX17, DNA methyltransferases, And esophageal squamous cell carcinoma